Issues with Treatment

Over the last decade there has been controversy in the medical community over treatment for borreliosis: one point of view is that it is easy to treat; the other that it needs aggressive treatment with antibiotics and other interventions. Until now, the first point of view has mostly prevailed in the UK medical community.

However, recent research at Northeastern University and John Hopkins University has shown that the bacterium which causes Lyme Disease forms dormant ‘persister’ cells, which are known to evade antibiotics. These make Lyme disease as difficult to treat as TB or leprosy. Treatment protocols needs to be modified to address the complexity of borrelia infection.

A recent retrospective study from the Netherlands concluded that "residual symptoms following treatment were found in 28.1% of patients, and risk of residual symptoms was significantly associated with delay from symptom debut to initiation of treatment".

Uncertainties

Many uncertainties exist which are not being acknowledged fully within NHS Scotland at present. The top 10 uncertainties in the diagnosis and treatment of Lyme Disease were agreed by clinicians and patients in a recent UK-based rigorous analysis by the UK Lyme Disease Priority Setting Partnership undertaken by Lyme Disease Action and the James Lind Alliance.

Existing Guidelines are Out-of-Date

Guidelines developed by the Infectious Diseases Society of America (IDSA) have been used for treatment in Scotland. These guidelines were developed in 2006, before the recent medical understanding of the complexities of borrelia and persistence. The IDSA guidelines have been removed from the US National Guidelines Clearinghouse because they are considered too out-of-date. IDSA have not produced more recent guidelines.

In September 2016, France became the first country to release a national plan to address tick-borne diseases like Lyme. It ranges from ramped-up surveillance of ticks and infections to better treatment protocols and diagnostic tests and specialist treatment centres. An interview with a leading French doctor explains how it evolved.

In March 2017, in Canada's Federal Framework on Lyme Disease Act they have stated "the current guidelines in Canada are based on those in the United States and are so restrictive as to severely limit the diagnosis of acute Lyme disease and deny the existence of continuing infection, thus abandoning sick people with a treatable illness". They have committed $4 milion to the framework.

It has taken 7 years following an Early Day Motion at Westminster to get agreement for development of such guidelines in England. Guidelines are in progress and a draft has been issued. However, they are narrow in scope, do not fully address persistence, do not include guidelines for co-infections, and some recommendations are based on no evidence whatsoever. Research recommendations include development of a core outcome set for clinical trials; research into incidence, features, management and outcomes; research into seroprevalence of co-infections in the UK; research into treatment options; and research into effective tests and biomarkers.

ILADS (the International Lyme and Associated Disease Society) has developed USA guidelines which do recognise the complexities of the disease and which are in the US National Guidelines Clearinghouse. German guidelines also exist which acknowledge issues with testing and the possibility of lack of response to treatment.

Late-Stage Borrelia Infection Involves Persistence

There is mounting evidence of bacterial persistence. As far back as 2013, it was stated that "accumulating evidence indicates that Lyme disease spirochetes are adapted to persist in immune competent hosts, and that they are able to remain infective despite aggressive antibiotic challenge. … Credible evidence supports the conclusion that LD can be a recalcitrant and chronic relapsing infection in animal hosts".

In 2015, research at Northeastern University found that "Borrelia burgdorferi, the causative agent of Lyme Disease, forms drug-tolerant persister cells".  Further research has concluded that there is “substantial evidence that Borrelia burgdorferi is capable of forming biofilm in vitro. Biofilm formation by Borrelia species might play an important role in their survival in diverse environmental conditions by providing refuge to individual cells.” In 2017, research at John Hopkins University found that even "ceftriaxone pulse dosing fails to eradicate biofilm-like microcolony B. burgdorferi persisters".

In a recent letter, it was stated that "There is 16S ribosomal RNA gene sequencing–based evidence of persistent infection by Borrelia burgdorferi and related spirochetes in patients after full courses of antibiotic treatment for Lyme disease. ... These cases proven by gene sequencing cannot be dismissed by the usual suspect of laboratory PCR contaminations."

Recent research found that "Borrelia burgdorferi manipulates innate and adaptive immunity to establish persistence in rodent reservoir hosts". Another paper reviews the mechanism of persistence via sleeper cells. Another study has found that extracellular, live spirochetes accumulate in lymph nodes and hypothesises that this tricks the immune system into making an inadequate response.

The evidence for proof of chronic lyme and its severity is discussed in a recent article.

One report cites over 700 papers that that support the evidence of persistence of Lyme and other tick-borne diseases.

Alternative Treatments are More Effective

Patient experience in Scotland is that, if treatment is offered, it normally involves giving doxycycline antibiotics, often for a period of up to one month in accordance with the IDSA guidelines. Serious cases are occasionally treated with 2-4 weeks of intravenous ceftriaxone. However, current treatment does not acknowledge persistence in long-term infection, for which much more effective treatment is emerging. Patients who have paid for private treatment abroad have recovered or obtained remission of infection through such treatments.

According to an article in Nature, "we identified 165 agents approved for use in other disease conditions that had more activity than doxycycline and amoxicillin against B. burgdorferi persisters. The top 27 drug candidates from the 165 hits were confirmed to have higher anti-persister activity than the current frontline antibiotics. Among the top 27 confirmed drug candidates from the 165 hits, daptomycin, clofazimine, carbomycin, sulfa drugs (e.g., sulfamethoxazole), and certain cephalosporins (e.g. cefoperazone) had the highest anti-persister activity. In addition, some drug candidates, such as daptomycin and clofazimine (which had the highest activity against non-growing persisters), had relatively poor activity or a high minimal inhibitory concentration (MIC) against growing B. burgdorferi. Our findings may have implications for the development of a more effective treatment for Lyme disease and for the relief of long-term symptoms that afflict some Lyme disease patients".

In a more recent study, it was found that "Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Microcolony B. burgdorferi Persisters Which Are Sterilized by Daptomycin/ Doxycycline/Cefuroxime without Pulse Dosing". Anecdotal evidence of recent clinical trials in the USA suggests treatment success is possible.

In an alternative study, “Dapsone is a novel and effective “persister” drug for those with PTLDS and associated tick-borne co-infections who have failed classical antibiotic protocols. Further prospective trials must determine the DDS dose, length of treatment and best combination antibiotic therapy in order to effect a long-term health benefit.”

Alternative Treatments may Include Natural Products

Natural products have been found to be useful in treating borreliosis and stevia shows promise. “The effectiveness of Stevia was compared to doxycycline, cefoperazone, daptomycin, and their combinations. Our results demonstrated that Stevia had significant effect in eliminating B. burgdorferi spirochetes and persisters. ... When Stevia and the three antibiotics were tested against attached biofilms, Stevia significantly reduced B. burgdorferi forms. Results from this study suggest that a natural product such as Stevia leaf extract could be considered as an effective agent against B. burgdorferi”.

In another study, “we tested the efficacy of 15 phytochemicals and micronutrients against three morphological forms of Borrelia burgdoferi and Borrelia garinii: spirochetes, latent rounded forms and biofilm. … The most effective antimicrobial compounds against all morphological forms of the two tested Borrelia sp. were baicalein and monolaurin. This might indicate that the presence of fatty acid and phenyl groups is important for comprehensive antibacterial activity. This study reveals the potential of phytochemicals as an important tool in the fight against the species of Borrelia causing Lyme disease.”

In very recent research into the antimicrobial activity of essential oils, "the top 5 essential oils (oregano, cinnamon bark, clove bud, citronella, and wintergreen) at a low concentration of 0.25% showed more activity than the persister drug daptomycin (40 microM). An interesting observation is that the highly active essential oils were found to have excellent anti-biofilm ability as shown by their ability to dissolve the aggregated biofilm-like structures."

Multiple Doses of Pulsed Treatment may be Required

In another study of persister cells, “we examined the ability of B. burgdorferi to form persisters. Killing of growing cultures of B. burgdorferi with antibiotics used to treat the disease was distinctly biphasic, with a small subpopulation of surviving cells. Upon regrowth, these cells formed a new subpopulation of antibiotic-tolerant cells, indicating that these are persisters rather than resistant mutants. The level of persisters increased sharply as the culture transitioned from exponential to stationary phase. Combinations of antibiotics did not improve killing. Daptomycin, a membrane-active bactericidal antibiotic, killed stationary phase cells, but not persisters. Mitomycin C, an anti-cancer agent that forms adducts with DNA, killed persisters and eradicated both growing and stationary cultures of B. burgdorferi. Finally, we examined the ability of pulse-dosing an antibiotic to eliminate persisters. After addition of ceftriaxone, the antibiotic was washed away, surviving persisters were allowed to resuscitate, and antibiotic was added again. Four pulse-doses of ceftriaxone killed persisters, eradicating all live bacteria in the culture.”

A review in 2013 concluded  that "future research on antibiotic treatment for LD in animal hosts should assess the effectiveness of pulsed, variable combinations of antibiotics for their abilities to disrupt the protective niches and evasive methods favored by these flexibly adaptive spirochetes. For example, use of a cephalosporin against spirochetal forms in the vascular compartment might be combined with pulsed dosing of tinidazole to cover spirochetal and atypical forms in matrix compartments. Such a regimen may yield better long-term outcomes than ceftriaxone or doxycycline alone."

Co-infections Make Treatment More Complex

Co-infection with other tick-borne pathogens is very common and has been found to increase the length and severity of illness. A survey run by Caudwell LymeCo is so far indicating that 94% of UK patients with Lyme disease believe they have at least one co-infection.  Examples of infections which can be transmitted by ticks at the same time as borrelia infection include bartonella, babesia, anaplasmosis, and erlichia.  Lyme Disease can also suppress the immune system and allow latent infections to come to the fore.  Examples include Epstein Barr and Herpes viruses. Some co-infections are developing antibiotic resistance and "reducing the level of immunosuppression when possible would appear to be a desirable strategy".

In a recent UK paper, it was suggested that patients who are chronically ill but seronegative "have a different disease from Lyme disease and therefore an alternative name, chronic arthropod-borne neuropathy (CAN), and case definition for this condition is proposed".